Coordination Chemistry Reviews
`148 (1996) 115-133
`
`7!!ilEN
`
`REVIEWS
`
`Preparation and structures of supramolecules between
`cyclodextrins and polymers
`
`Akira Harada
`Department of Macromolecular Science, Faculty of Science, Osaka Uniuersity, Toyonaka, Osaka 560, Japan
`
`Received 1 February
`
`Contents
`
`...................................................
`Abstract
`..............................................
`1. Introduction
`.............
`2. Complex formation between cyclodextrins and hydrophilic polymers
`2.1. Complex formation of a-cyclodextrin with poly(ethylene glycol) .............
`..............................
`2.1.1. Rates of complex formation
`2.1.2. Effects of the molecular weight of polymers on the yield of the complexes ...
`...........................
`2.1.3. Stoichiometries of the complexes
`..............................
`2.1.4. Properties of the complexes
`.....................................
`2.1.5. Inclusion modes
`2.1.6. Complex formation between cyclodextrin and poly(ethylene glycol) derivatives
`..................
`2.1.7. Synthesis of molecular necklace (polyrotaxanes)
`2.3. Complex formation of cc-cyclodextrin with monodisperse oligo(ethylene glycol)s
`2.4. Synthesis of a polyrotaxane containing monodisperse oligo(ethylene glycol) ......
`......
`2.5. Complex formation of j- and y- cyclodextrins with poly(propylene glycol)
`2.6. Complex formation between y-cyclodextrin and poly(methy1 vinyl ether) ........
`...............
`3. Complex formation of cyclodextrins with hydrophobic polymers
`.................
`3.1. Complex formation of oligoethylene with cc-cyclodextrin
`................
`3.2. Complex formation of polyisobutylene with y-cyclodextrin
`...............................................
`4. Conclusions
`References..
`................................................
`
`...
`
`115
`116
`117
`117
`117
`118
`119
`120
`121
`121
`124
`126
`128
`128
`129
`130
`130
`130
`131
`132
`
`Abstract
`
`(CDs) form inclusion complexes with various polymers with high selectivit-
`Cyclodextrins
`ies to give crystalline compounds. N-CD formed complexes with poly(ethylene glycol) (PEG)
`and oligoethylene
`in high yields, although /?-CD did not form complexes with PEG. However,
`/?-CD formed complexes with poly(propylene
`glycol) (PPG). Although LX-CD did not form
`complexes with polyisobutylene
`(PIB) and poly(methy1 vinyl ether) (PMVE), y-CD formed
`complexes with PIB and PMVE. There is a good correlation between the sectional areas of
`the polymers and the sizes of the CDs. The stoichiometries, properties, and structures of the
`
`OOlO-8545/96/$32.00 0 1996 Elsevier Science S.A. All rights reserved
`SSDI OOlO-8545(95)01157-9
`
`ARGENTUM PHARM. 1018
`
`000001
`
`

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`A. Harada/Coordination Chemistry Reviews 148 (1996) 115-133
`
`increased with increasing molecular
`complexes are discussed. The yield of the complexes
`weight. Polyrotaxanes,
`in which many cyclodextrins are threaded on a poly(ethylene glycol)
`chain, were prepared by capping
`the chain ends of the polymers
`in the complexes with
`bulky groups.
`
`Keywords:
`
`Supramolecules; Cyclodextrins; Polymers
`
`1. Introduction
`
`In recent years, much attention has been focused on molecular recognition of low
`molecular weight compounds Cl]. Crown ethers [2], cryptands
`[3], cyclophanes
`[4], and calixarenes
`[S] have been extensively used as host molecules. However,
`the guests recognized by these host molecules have been limited to small molecules
`and simple ions, such as lithium, sodium, potassium, chloroform, and benzene. Host
`molecules which can recognize and respond sensitively to larger and more compli-
`cated compounds and even polymers are required.
`antigen-antibodies, DNA, RNA,
`In biological systems such as enzymes-substrates,
`recognition,
`that is, recognition
`and cell adhesion systems, however, macromolecular
`of macromolecules
`by macromolecules,
`plays an important
`role in constructing
`supramolecular structures and maintaining
`their lives [ 61. However, there have been
`no approaches
`toward macromolecular
`recognition by artificial host-guest systems.
`Since cyclodextrins were discovered, a great number of reports (more than 10000
`papers) have been published on cyclodextrins. However, studies on the inclusion
`properties of cyclodextrins were limited to those with low molecular weight com-
`pounds [7-g]. Cyclodextrins are cyclic molecules consisting of six to eight glucose
`units
`linking
`through a-1-4-glycosidic
`linkages. They are called CI-, p-, and y-
`cyclodextrin
`(CD), respectively. They are known to form inclusion complexes with
`a wide variety of low molecular weight compounds,
`ranging from nonpolar hydro-
`carbons
`to polar carboxylic acids and amines. There have been no reports on the
`complex formation of cyclodextrins with polymers when we started our work in
`early 1980s. Therefore, we have started our project on complex formation between
`polymers and cyclodextrins.
`in situ
`There have been some examples in which a monomer was polymerized
`within a cyclodextrin complex. Ogata et al. prepared hexamethylene diamine com-
`plexes of B-CD [lo]. Polyamides were obtained by condensation of dibasic acid
`chlorides and the inclusion complexes of the diamine. Maciejewski reported
`the
`polymerization
`and copolymerization
`of vinylidene chlorides as adducts with B-CD
`[ll]. There are some reports which suggest interactions between cyclodextrins and
`some polymers in aqueous solutions. Kitano et al. reported
`that cyclodextrins show
`some effects on the critical micelle concentrations of some micelle-forming surfactants
`[ 121. Iijima et al. studied diffusion of cyclodextrin
`in the presence of poly(styrenesul-
`fonate) in aqueous solutions and reported
`that there are some interactions between
`cyclodextrin and the polymer [13].
`the formation of
`There have recently been reports by Gibson et al. describing
`supramolecular complexes bewteen crown ethers and oligomers [ 141.
`
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`A. HaradalCoordination Chemistry Reviews 148 (1996) 115-133
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`
`Table 1
`Complex formation of CDs with hydrophilic polymers
`
`Polymer
`
`Structure
`
`MW
`
`Yield (%)
`
`PVA
`
`PAAm
`
`PEG
`PPG
`
`PMVE
`
`- (CH,CH)
`I
`
`- (CH,::)
`I
`CONHl
`- (CH,CH,O)-
`- (CH,CHO)
`I
`
`- (CH,::;
`I
`OCH,
`
`a-CD
`
`B-CD
`
`y-CD
`
`22 000
`
`10000
`
`1000
`1000
`
`20000
`
`0
`
`0
`
`92
`0
`
`0
`
`0
`
`0
`
`0
`96
`
`0
`
`0
`
`0
`
`trace
`80
`
`80
`
`2. Complex formation between cyclodextrins and hydrophilic polymers [ 151
`
`We tested whether cyclodextrins would form complexes with some water-soluble
`nonionic polymers. Table 1 shows the results of the formation of complexes of
`cyclodextrins with some nonionic polymers. We found that cyclodextrins did not
`form complexes with some nonionic water-soluble polymers
`(such as poly(viny1
`alcohol) (PVA) and polyacrylamide
`(PAAm)) by the same procedure as that for low
`molecular weight compounds. However, we found that a-CD forms crystalline com-
`plexes with poly(ethylene glycol) (PEG) in high yield.
`
`2.1. Complex formation of cz-cyclodextrin with poly(ethylene glycol) [16]
`
`When aqueous solutions of PEG were added to a saturated aqueous solution of
`a-CD at room
`temperature
`the solution became turbid and the complexes were
`formed as precipitates when the average molecular weight of PEG was more than
`200. [17]
`
`2.1 .I. Rates of complex formation
`While preparing
`the complexes of a-CD with PEG we found that the rate of
`complex formation depends on the molecular weight of PEG. Fig. 1 shows the effects
`of molecular weights on the rate of turbidity development after mixing the saturated
`a-CD solution and PEG solution. The figure clearly shows that PEG of molecular
`weight 1000 forms complexes most rapidly. This may be partly due to the fact that
`the number of end groups decreases as the molecular weight increases. Addition of
`the PEG solution to a saturated aqueous solution of P-CD did not cause any change
`in solution.
`
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`A. Haradajcoordination Chemistry Reviews 148 (1996) 115-133
`
`Fig. 1. Effects of molecular weight on the rate of turbidity development after mixing the saturated a-CD
`and PEG solutions.
`
`2.1.2. EfSects of the molecular weight of polymers on the yields of the complexes [ 1 S]
`The complexes were isolated by filtration or centrifugation. Fig. 2 shows the yields
`of the complexes of a-CD with PEG of various molecular weights. The yields are
`calculated on the basis of 2 : 1 (ethylene glycol unit : a-CD) stoichiometry, as discussed
`in the following section. a-CD did not form complexes with the low molecular weight
`analogs ethylene glycol, diethylene glycol, and triethylene glycol. a-CD formed com-
`plexes with PEG of molecular weight > 200. The yields were found to increase with
`
`20-
`
`;
`
`0
`
`0
`
`400
`
`800
`
`1200
`
`1600
`
`2(
`
`IO
`
`Mn of PEG
`
`Fig. 2. Yields of the complexes of N-CD with PEG as a function of the molecular weight of PEG.
`
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`A. HaradalCoordination Chemistry Reviews 148 (1996) 115-133
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`119
`
`increasing molecular weight. The complexes were obtained almost quantitatively
`with PEG of molecular weight > 1000. P-CD did not form complexes with PEG of
`any molecular weight. Although PEG of molecular weight B 1000 formed complexes
`with a-CD slowly, they gave high yields after several hours.
`This observation
`that a minimum PEG length is required for the formation of
`stable cyclodextrin complexes shows the importance of cooperativity
`in complexation
`and is similar to the formation of PEG complexes with hydrogen-donor
`polymers
`such as poly(acrylic acid).
`
`2.1.3. Stoichiometries of the complexes
`The complex formation of U-CD with PEG was studied quantitatively. Fig. 3
`shows the yields of the complexes of a-CD with PEG of average molecular weight
`600 as a function of added PEG. The yields increased linearly when the amount of
`PEG added was small and leveled off at a molar ratio of 2: 1 (ethylene glycol
`is stoichiometric. The
`unit : CD). These results indicate that the complex formation
`saturation values show that more than 90% of the a-CD was consumed by the
`complex formation with PEG. The continuous variation plots for the complexation
`between a-CD and PEG also suggest that the stoichiometries of the complexes are
`all 2: 1. The stoichiometries were confirmed by the ‘H NMR spectrum. Fig. 4 shows
`the ‘H NMR spectrum of the complex of PEG-600 with cl-CD. It should be noted
`that the stoichiometries of the complexes are always 2 : 1 even if a-CD and PEG are
`mixed in any ratio. The length of two ethylene glycol units corresponds
`to the depth
`of the cavity of a-CD.
`Carbohydrate
`polymers such as dextran and pullulan did not form insoluble
`complexes with PEG. Amylose and dextrin also did not form insoluble complexes
`with PEG. Glucose, methyl glycoside, maltose, and maltotriose
`did not form
`
`0
`
`4
`
`8
`
`PEG (Mol x 104)
`
`Fig. 3. Amount
`2 ml of saturated
`
`as a function of added PEG
`complexes
`of a-CD-PEG
`aqueous
`solution of a-CD was used.
`
`(MW=600).
`
`A total amount
`
`of
`
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`A. HaraabJCoordination Chemistry Reviews 148 (19%) 115-133
`
`5.0
`
`4.5
`
`4.0
`
`3.5
`
`Fig. 4. ‘H NMR spectra of the complexes of PEG with (a) U-CD and (b) a-CD in D,O.
`
`complexes with PEG. Cyclodextrin derivatives, such as glucosyl-a-CD and maltosyl-
`a-CD, and soluble polymers of a-CD, did not form insoluble complexes with PEG.
`
`2.1.4. Properties of the complexes
`The complexes of a-CD with PEG of low molecular weight (1000) are soluble in
`water. The complexes of PEG of higher molecular weight can be dissolved in water
`by heating. The addition of an excess amount of a low molecular weight guest, such
`as benzoic acid, propionic acid, and propanol,
`to the suspension of the complex
`resulted in solubilization of the complex when the molecular weight of PEG was
`low (1000). The formation of the complex is reversible. In solution, complexes are
`in equilibrium between the complex and its component. The addition of salts such
`as NaCl and KC1 did not cause any change in the solubility of the complexes. This
`result indicates that there are no ionic interactions between a-CD and the polymer.
`The addition of urea, which is thought to affect hydrogen bonds, results in solubiliza-
`tion of the complexes, indicating that hydrogen bonding plays an important
`role in
`forming the complexes between PEG and a-CD.
`The decomposition points of the complexes are a little higher than that of the
`cyclodextrin. The complex of a-CD with PEG-1000 decomposes above 3OO”C,
`
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`121
`
`whereas a-CD melts and decomposes below 300°C. Thus, poly(ethylene glycol)
`stabilizes U-CD.
`
`2.1.5. Inclusion modes
`Fig. 5 shows the X-ray powder patterns of the complex of a-CD with PEG and
`those with other low molecular weight compounds. Saenger et al. reported
`that the
`structures of the inclusion complexes of CDs with low molecular weight compounds
`can be classified into two groups: ‘cage-type’ and ‘channel-type’ [9]. The X-ray
`powder pattern of the a-CD-PEG complex shows that the complexes are crystalline.
`The patterns are very similar to those of the complex of a-CD with valeric acid or
`octanol, which have been reported to have an extended column structure, and totally
`different from those of the complexes with small molecules such as acetic acid,
`propionic acid, and propanol, which have a cage-type structure. These results indicate
`that the complexes of a-CD and PEG are isomorphous with those of channel-type
`rather than cage-type structure.
`Molecular models show that PEG chains are able to penetrate a-CD cavities,
`while the poly(propylene glycol) chain cannot pass through the a-CD cavity. These
`views are in accordance with our observation
`that a-CD forms complexes with PEG
`but not with poly(propylene
`glycol). /I-CD did not form complexes with PEG. A
`PEG chain is too slim to fit in the /?-CD cavity. However, P-CD forms complexes
`with poly(propylene
`glycol). Model studies indicate furthe!
`that the single cavity
`(depth 6.7 A) accommodates
`two ethylene glycol units (6.6 A) when ethylene glycol
`chain assumes a planar zigzag conformation.
`Fig. 6 shows the 13C CP/MAS NMR spectra of a-CD and the a-CD-PEG complex.
`a-CD assumes a less symmetrical conformation
`in the crystal when it does not
`include a guest in the cavity. In this case, the spectrum shows resolved C-l and C-4
`resonances from each of the six a-1,4-linked glucose residues. In particular, C-l and
`C-4 adjacent
`to a conformationally
`strained glycosidic linkage are observed at 80
`and 98 ppm, respectively. In the spectrum of the a-CD-PEG complex, however, the
`peaks at 80 and 98 ppm disappeared. Each carbon of glucose can be observed in a
`single peak. These results indicate that a-CD adopts a symmetrical conformation
`and each glucose unit of CD is in a similar environment. The X-ray studies of single
`crystals showed that a-CD assumes a less symmetrical conformation when it does
`not include guests in the cavity and a-CD adopts a symmetrical conformation when
`it includes guests in the cavities. CP/MAS NMR spectra of complexed and uncom-
`plexed CDs are consistent with the X-ray results. So a PEG chain is thought to be
`included in the cavities.
`
`2.1.6. Complex formation between cyclodextrin and poly(ethybne glycol) derivatives
`Table 2 shows results of complex formation between a-CD and PEG with various
`end groups. First, PEGS with small end groups such as methyl, dimethyl, and amino
`groups, form complexes. The yields are somewhat higher than with unmodified PEG.
`This result indicates that interactions
`(hydrogen bonds) between the OH groups of
`OEG and those of a-CD are not the driving force for complex formation.
`
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`10.01
`
`2 u
`
`s.00
`
`% 5.01
`
`OL-CD-CH3CH2C02H
`
`3L-CO-CH3(CH2
`
`)+02H
`
`a-CD-PEG(
`
`1000 1
`
`3.00
`
`Fig. 5. X-Ray diffraction patterns for a-CD complexes: (a) a-CD-propionic acid; (b) u-CD-valeric acid;
`and (c) N-CD-PEG (MW = 1000).
`
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`A. HaradaJCoordination Chemistry Reviews 148 (1996) 115-133
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`123
`
`and C-4
`C-i
`conlorhationally
`glycosidic
`linkage
`
`lo a single,
`adjacent
`strained
`
`(b) a-CD-PEG
`
`Complex
`
`‘3C CP/MAS NMR
`Fig. 6. 13C CP/MAS NMR spectra of (a) a-CD and (b) the u-CD-PEG
`
`complex.
`
`PEG carrying bulky substituents at either end of the PEG which do not fit or
`pass through
`the a-CD cavity, such as 3,5-dinitrobenzoyl
`and 2,4-dinitrophenyl
`groups, did not form any complexes with U-CD.
`Fig. 7 shows a proposed structure of the complex of poly(ethylene glycol) with
`E-CD. The inclusion complex formation of PEG in the U-CD channel is entropically
`unfavorable, However, formation of the complexes is thought
`to be promoted by
`hydrogen bond formation between neighboring cyclodextrins. Therefore, head-to-
`head and tail-to-tail arrangements are thought to be the most probable structures.
`
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`A. HaraakjCoordination
`
`Chemistry Reviews 148 (1996) 115-133
`
`Table 2
`Complex formation between CD and PEG with various end groups
`
`R(CH,CH,O)“CH,CH,R’
`
`Yield (%)
`
`MW
`
`X-CD
`
`D-CD
`
`90
`90
`93
`
`0
`
`77
`
`0
`
`0
`0
`0
`
`0
`
`10
`
`0
`
`R
`
`-OH
`-NH,
`-OCH,
`
`R
`
`-OH
`-NH,
`-OCH,
`
`1000
`1450
`1000
`
`02
`
`02N
`
`02
`
`3700
`
`a-CD
`
`Fig. 7. Proposed structure of the a-CD-PEG complex.
`
`[ 19-211
`2.1.7. Synthesis of molecular necklace (polyrotaxanes)
`science, science of
`Recently, much attention has been focused on supramolecular
`noncovalent
`assembly, because of the recognition of the importance of specific
`noncovalent
`interactions
`in biological systems and in chemical processes
`[22].
`Rotaxanes are one of the classical classes of molecules consisting of noncovalent
`entities, with a ‘rotor’ and an ‘axle’ in a single molecule [ 231. They were synthesized
`in a statistical way, but yields were very low [24]. More recently, rotaxanes have
`attracted
`renewed interest in the field of supramolecular chemistry because of their
`unique structures and properties. Rotaxanes can be prepared by closing the end
`groups of ‘axle’ using large groups within the ordered environments of the noncova-
`lent ternplating forces in such a way as to retain the order originally imposed by the
`weak interactions
`[ 251. By this method complexes containing methylated
`/?-CD and
`
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`
`Chemistry Reviews 148 (1996) 115-133
`
`125
`
`threads [ 26-271 have been synthesized. Both symmetric [28-291 and asymmetric
`[ 301 ionic rotaxanes containing cr-CD have been reported (Fig. 8).
`We have succeeded
`in preparing compounds
`in which many cyclodextrins are
`threaded on a single PEG chain. They are trapped by capping the chain ends with
`bulky groups, as shown in Scheme 1. This is the first example in which many rotors
`are imprisoned
`in a single molecule. We named this molecule ‘molecular necklace’.
`Wenz and Keller also reported a rotaxane with many a-CDs [31].
`The inclusion complexes of a-CD with PEG bisamine (PEG-BA) were prepared
`by adding an aqueous solution of PEG-BA to a saturated aqueous solution of c.+CD
`at room temperature, using a method similar to that used to prepare complexes of
`a-CD and PEG. The resulting complex was allowed to react with an excess of
`2,4-dinitrofluorobenzene, which is bulky enough to prevent unthreading. The product
`was purified by column chromatography on Sephadex G-50 using dimethylsulfoxide
`(DMSO) as solvent.
`The products are insoluble in water and dimethylformamide, but are soluble in
`DMSO and in 0.1 N NaOH. The products were characterized by UV-vis, X-ray
`diffraction, ‘H NMR, 13C NMR 13C CP/MAS NMR and 2D NOESY NMR spec-
`troscopies. The ‘H NMR spectra of the product shows that it is composed of a-CD,
`
`Fig. 8. Symmetric and asymmetric [2]-rotaxanes.
`
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`A. Haradalcoordination Chemistry Reviews 148 (1996) 115-133
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`H2N+2 HzC H+C
`
`H& HPN H2
`
`OzN~NH~NH~Nq
`NO2
`
`NO2
`
`Scheme 1.
`
`PEG-BA, and dinitrophenyl groups and the peaks of CD, PEG, and dinitrophenyl
`groups are broadened, suggesting that a-CDs move with difficulty on a PEG chain.
`2D NOESY NMR spectra show that the signals of H-3 and H-5 protons of a-CD,
`which are directed toward the inside of the cavity, correlate with the resonance of
`the CH2 of PEG, but the H-l, H-2, and H-4 protons, which are located outside the
`cavity, do not correlate with PEG. These results indicate
`that a PEG chain is
`included in the a-CD cavities.
`Table 3 shows the results of the preparation of polyrotaxanes of various molecular
`weights. The number of CDs increases with increasing molecular weight. MN-3350,
`which was prepared from PEG (MW = 3350), has 20-23 CDs on a PEG chain. This
`corresponds
`to a molar ratio of ethylene glycol units to a-CDs of 3.9. More than
`half of the polymer chain is covered with a-!-CDs. MN-1450 has 15 a-CDs on a PEG
`chain. The molar ratio of ethylene glycol units to a-CD is 2.3. This ratio indicates
`that the complex is almost stoichiometric,
`i.e. the CDs are packed from end to end
`of the polymer chain to almost the closest possible extent.
`
`2.3. Complex formation of a-cyclodextrin with monodisperse oligo(ethylene glycol)s
`[321
`
`available PEGS which are polydisperse.
`We have used so far commercially
`Therefore,
`the complexes obtained were polydisperse and heterogeneous. We also
`
`Table 3
`Molecular weight and composition of polyrotaxanes
`
`Polyrotaxane
`
`MW
`
`No. of ethylene
`glycol unit
`
`No. of a-CD
`included
`
`Molar ratio between ethylene
`glycol units and U-CD
`
`MN-3350
`MN-2000
`MN*-2001”
`MN-1450
`
`23500
`20000
`19000
`16 500
`
`77
`45
`45
`35
`
`B Prepared from JED-2001.
`
`20
`18
`17
`15
`
`3.9
`2.5
`2.6
`2.3
`
`000012
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`A. HaradalCoordination Chemistry Reviews 148 (1996) 115-133
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`
`found that a-CD did not form complexes with low molecular weight analogs, such
`as ethylene glycol and bis(ethylene glycol). In order to make clear the chain-length
`selectivity and to obtain pure monodisperse complexes we prepared monodisperse
`oligo(ethylene glycol)s (OEG) and studied the interactions between cl-CD and the
`pure oligo(ethylene glycol)s.
`(n = 8, 12, 28, 20, 28, 36, 44) were
`Oligo(ethylene glycol)s HO(-CH,CH,O)n-OH
`prepared by stepwise reactions starting from a,o-tetrakis(ethylene
`glycol) ditosylate
`and the monosodium
`tosylate using Bomer’s method. The products were purified
`repeatedly by preparative size-exclusion chromatography
`(SEC).
`Fig. 9 shows the yields of the complexes of R-CD with OEG as a function of the
`degree of polymerization of OEG. The yields are calculated on the basis of 2 : 1
`stoichiometry.
`a-CD did not form complexes with ethylene glycol, bis(ethylene
`glycol), and tris(ethylene glycol). cl-CD formed complexes with tetrakis(ethylene
`glycol) (TEG) and larger OEG. The yields increase sharply with increasing degree
`of polymerization
`from 5 to 12. The complexes were obtained almost quantitatively
`with eicosakis(ethylene glycol) and larger OEG. P-CD did not form complexes with
`any OEG. The stoichiometries of the complexes are all 2: 1 (two ethylene glycol
`units and one U-CD) when the degree of polymerization
`is >6. The stoichiometries
`of the complexes of a-CD with TEG and pentakis(ethylene glycol) (PEG) are 2:l
`(CD:OEG).
`Table 4 shows the results of complex formation between U-CD and cyclic oligomers
`of ethylene glycol together with those of linear OEG for comparison. It is interesting
`that the yields of the complexes of a-CD with cyclic OEG decreased as the size of
`the guest increased, and those of the complexes of a-CD with linear OEG increased
`with increasing chain length. Cyclic oligomers of ethylene glycol (crown ethers,
`15crown-5
`and 18-crown-6) did not
`form complexes with c&D,
`except
`for
`
`30
`20
`10
`0
`Degree of polymerization
`
`40
`of PEG
`
`50
`
`Fig. 9. Yields of the complexes of a-CD with oligo(ethylene glycol) as a function of the degree of
`polymerization.
`
`000013
`
`

`
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`
`Table 4
`Yields (%) or complex formation of linear and cyclic oligo(ethylene glycol) with a-CD*
`
`Number of -CH2 CH*O-
`
`2
`
`0
`21
`
`3
`
`0
`
`4
`
`2
`9
`
`5
`
`9
`0
`
`6
`
`30
`0
`
`I
`
`56
`-
`
`8
`
`64
`-
`
`12
`
`16
`-
`
`Linear
`Cyclic
`
`’ Complexes formed at 25°C.
`
`12-crown-4 which gave complexes with cr-CD in low yield. These crown ethers are
`too large to fit in the CD cavity and a-CDs are not able to penetrate
`the chain
`owing to the absence of the chain ends. These results indicate that end groups are
`required for complex formation.
`
`2.4. Synthesis of a polyrotaxane containing monodisperse oligo(ethylene glycol) [33]
`
`containing many a-CDs was
`of polyrotaxanes
`In Section 2.2 the preparation
`described. However, in this case the polymers used are polydisperse and the number
`of CDs in a polymer chain is also polydisperse. The rotaxanes obtained by this
`method are highly heterogeneous. Moreover,
`in both rotaxanes only part of the
`polymer chain is covered with cyclodextrins. In order to obtain homogeneous polyro-
`taxanes we have prepared monodisperse PEGS (28mer, MW = 1248) because PEGS
`of molecular weight 1000-1500 were found to be most favorable for complex forma-
`tion. We have succeeded in preparing complexes between a-CDs and monodisperse
`diamino-PEG
`and imprisoning
`twelve a-CDs on monodisperse diamino-PEG
`by
`capping PEG chain ends with bulky substituents. It is an important step toward the
`‘molecular abacus’.
`shows that the C-4 and C-6 peaks
`The 13C NMR spectrum of the polyrotaxane
`are doublets; a broad peak at a higher magnetic field and a sharper peak at a lower
`field, respectively. The broad peaks can be assigned to C-6 and C-4 in the rotaxane,
`which move with difficulty due to hydrogen bonds between CDs. The sharp peaks
`at lower magnetic field can be assigned to C-6 and C-4 of the cyclodextrins at both
`ends because they are not involved in hydrogen bonds and are more flexible than
`the others and they are susceptible to the effects of the dinitrophenyl groups at the
`ends of the rotaxane.
`The bulky end groups (dinitrophenyl groups) were removed by cleaving the C-N
`bond with strong base, and the CDs were recovered. The number of cyclodextrins
`in the polyrotaxane
`can be estimated from the ‘H NMR spectra, optical rotation,
`and UV-vis spectra. Twelve a-CDs were found to be included in the polyrotaxane.
`
`2.5. Complex formation of fi- and y-cyclodextrins with poly(propylene glycol) [34]
`
`/?-CD was found to form
`P-CD does not form complexes with PEG. However,
`complexes with poly(propylene glycol) (PPG), which has methyl groups on a PEG
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`A. Haradafcoordination Chemistry Reviews 148 (1996) 115-133
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`129
`
`loo-
`
`z
`u
`5
`>
`
`60-
`
`40-
`
`I
`
`0
`
`1000
`
`2000
`
`3000
`
`4000
`
`5000
`
`MW of PPG
`
`Fig. 10. Yields of the complexes of j3-CD with PPG as a function of the molecular weight of PPG.
`
`chain, to give crystalline compounds. a-CD does not form complexes with PPG of
`any molecular weight. There is a good correlation between the sectional area of
`polymers and the sizes of CD cavities. Fig. 10 shows the yields of the complexes of
`P-CD with PPG molecules of various molecular weights. P-CD does not form
`complexes with the dimer and trimer, but forms complexes with PPG of molecular
`weight >400. The yields increase with increasing molecular weight of PPG. The
`complexes were obtained almost quantitatively with PPG of molecular weight about
`1000. However, the yields decrease with increasing molecular weight of PPG. y-CD
`also forms complexes with PPG in high yields even when the molecular weight of
`PPG is low (400-725). The stoichiometries are again 2: 1 (two propylene units per
`CD). Molecular model studies show that PPG chains are able to penetrate P-CD
`cavities, while the PPG chain cannot pass through
`the U-CD cavity owing to the
`hindrance of the methyl group on the main chain. These views are in accordance
`with our results that /?-CD forms complexes with PPG but a-CD does not form
`complexes with PPG. Model studies indicate further that the single cavity accommo-
`dates two propylene glycol units.
`
`2.6. Complex formation between y-cyclodextrin and poly(methy1 vinyl ether) [35]
`
`Poly(methy1 vinyl ether), which has the same composition as that of PPG but
`with methoxy groups as side chains, did not form complexes with a- and B-CDs.
`However, it formed complexes with y-CD, which has the largest cavity in the series
`of CDs. In this case the stoichiometry
`is 3 : 1 (monomer units : CD). The number of
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`
`atoms in the main chain included in a single CD is six, which is the same as for
`a-CD-PEG and B-CD-PPG complexes.
`
`3. Complex formation of cyclodextrins with hydrophobic polymers
`
`form complexes not only with hydrophilic polymers
`We found that cyclodextrins
`but also with hydrophobic
`polymers such as oligoethylene and polyisobutylene.
`Table 5 shows the yields of the complexes formed by cyclodextrins and some hydro-
`phobic polymers. a-CD forms complexes with oligoethylenes, although /?- and Y-CD
`did not form complexes with oligoethylenes under the same conditions. However, j?-
`and y-CD formed complexes with polyisobutylene
`(PIB), although U-CD did not.
`
`3.1. Complex formation of oligoethylene with a-cyclodextrin [36]
`
`(OE) was found to form inclusion complexes with cr-CD not only
`Oligoethylene
`from aqueous solutions of a-CD but also from DMF solutions of a-CD to give
`stoichiometric crystalline compounds
`in high yield. The yields depend on the degree
`of oligomerization of OE when DMF was used as solvent. OE with n ~6 did not
`form complexes with U-CD in DMF solution. The complexes have stoichiometries
`studies and
`i3C CP/MAS and
`of 3 : 1 (ethylene unit: a-CD). X-Ray diffraction
`PST/MAS NMR spectra suggest that the OE chain is included in the channel formed
`by a-CDs and the OE backbone
`in the complexes
`is more flexible than that in
`uncomplexed state.
`
`3.2. Complex formation of polyisobutylene with y-cyclodextrin [37]
`
`Fig. 11 shows the yields of the complexes of PIB with B-CD and Y-CD as a
`function of the molecular weight of PIB. c&D did not form complexes with PIB of
`
`Table 5
`Formation of solid-state complexes between cyclodextrins and hydrophobic polymers/oligomers with
`various chain sectional areas
`
`Polymer/oligomer
`
`Structure
`
`MW
`
`Yield (%)
`
`OE( 20)
`squalane
`
`PIB
`
`-CH,CH,-
`-CH,CHCH#H,-
`
`A-I,
`?I&
`
`-CH,C-
`
`CH,
`
`a-CD
`
`/?-CD
`
`?-CD
`
`563
`423
`
`-800
`
`63
`0
`
`0
`
`0
`62
`
`8
`
`0
`24
`
`90
`
`000016
`
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`
`A. HaraaizlCoordination Chemistry Reviews 148 (1996) 11.5-133
`
`131
`
`Polyisobutylene(PIB)
`
`Fig. 11. Yields of the complexes of CDs with PIB as a function of the molecular weight of PIB.
`
`MW
`
`any molecular weight. The yields of the complexes with /?-CD decreased with increas-
`ing molecular weight of PIB. In contrast,
`the yields of the complexes with y-CD
`increased with increasing molecular weight and the complexes were obtained almost
`quantitatively with PIB of molecular weight of 1000. The chain length selectivity is
`totally reversed between /?-CD and y-CD. In particular,
`/?-CD formed complexes
`with the low molecular weight analogs, monomer and dimer; y-CD did not form
`complexes with these low molecular weight compounds.
`
`4. Conclusions
`
`Cyclodextrin were found to form inclusion complexes not only with low molecular
`weight compounds but also with hydrophilic polymers and hydrophobic polymers
`to give stoichiometric compounds
`in high yield. The selectivities shown by cyclo-
`dextrins toward polymers are much higher than for low molecular weight compounds.
`This is due to the fact that the guest polymers have a lot of recognition sites and
`
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`
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`
`A. Haraab/Coordination Chemistry Reviews 148 (1996) 115-133
`
`the recognition processes are repeated. This is one of the reasons why the living
`systems are composed of many kinds of macromolecules. This kind of complex
`formation can be utilized to create new supramolecular architectures and functions
`[38-411.
`
`References
`
`[1] A. Harada, in P. Zanello (Ed.), Stereochemistry of Organometallic and Inorganic Compounds,
`Vol. 5, Chains, Clusters, Inclusion Compounds, Paramagnetic Labels, and Organic Rings, Elsevier,
`1994, p. 409.
`[Z] C.J. Pedersen, J. Am. Chem. Sot., 89 (1967) 2495.
`[ 31 J.-M. Lehn, Angew. Chem. Int. Ed. Engl., 27 (1988) 89.
`[4] D.J. Cram, Nature, 356 (1992) 29.
`[ 51 S. Shinkai, Tetrahedron, 49 (1993) 8933.
`[6] A. Harada, Yukagaku, 43 (1994) 839.
`[7] M.L. Bender and M. Komiyama, Cyclodextrin Chemistry, Springer-Verlag, Berlin, 1978.
`[S] J. Sxejtli, Cyclodex